{"paper_id":"38dd254e-5062-47aa-a7f2-b3f93443326d","body_text":"One of the most prevalent causes of an acute abdomen requiring surgical excision is\nappendicitis, an inflammation of the vestigial vermiform appendix which is confirmed\nby histopathologic studies [ 1 ]. Many\ninfectious and noninfectious etiologies (e.g., fecaliths, tumors, lymphoid\nhyperplasia, and so on) are associated with appendicitis [ 2 ]. The main cause of acute appendicitis is obstruction of the\nlumen of the appendix, which affects around 7% of the population. An obstruction\ncaused by parasites in the large intestine and appendix can lead to appendicitis. If\nthe lumen is obstructed by parasites or their ova, appendicitis may develop. The\nmost frequent findings in the majority of investigations on histopathological\nvariations in acute appendicitis due to the parasites were a relatively high\nfrequency of polymorphonuclear leukocytes (PMNs) infiltration and suppurative\nexudate [ 3 ].\nAppendicitis can affect anyone of any age, however, it affects men more commonly than\nwomen and most cases are seen in patients aged 10 - 40 [ 1 ][ 2 ]. The function of E.\nvermicularis in the pathogenesis of appendicitis has been controversial since the\nfirst report of the presence of this parasite in the appendix lumen in the late\nnineteenth century [ 1 ][ 3 ][ 4 ][ 5 ][ \n6 ][ 7 ][ 8 ][ 9 ][ 10 ][ 11 ][ 12 ][ 13 ][ 14 ][ 15 ][ 16 ][ 17 ][ 18 ][ 19 ][ 20 ][ 21 ][ 22 ][ 23 ][ 24 ][ 25 ][ 26 ][ 27 ][ 28 ][ 29 ][ 30 ][ 31 ][ 32 ][ 33 ][ 34 ][ 35 ][ 36 ][ 37 ][ 38 ][ 39 ][ 40 ][ 41 ][ 42 ][ 43 ][ 44 ][ 45 ][ 46 ][ 47 ][ 48 ][ 49 ].\nOnly a few intestinal parasites belonging to both groups, the protozoa and helminths\nacutely penetrate, or attach to the mucosal lining of the appendicular wall, and can\nbe identified in appendicitis etiology [ 3 ].\nGiardia lamblia, Entamoeba histolytica, Enterobius vermicularis, Ascaris\nlumbricoides, Taenia spp., Strongyloides stercoralis, Trichuris trichiura, and\nSchistosoma spp. are parasites that have been reported can lead to a clinical\npicture of acute appendicitis. Globally distributed E. vermicularis (Syn. Oxyuris,\npinworm), is considered the most frequently parasitic cause of appendicitis [ 2 ][ \n3 ][ 4 ]. Although E. vermicularis\nalone is identified in about 0.2% to 15% of the excised appendices, its actual\nability to injure mucosa has widely been discussed [ \n2 ].\nUnfortunately, the importance of parasitic etiologies in the pathogenesis of\nappendicitis is not well known in appendectomy specimens on a large scale in Iran.\nThis study aimed a retrospective review of tissue sections of appendectomy specimens\nto determine the prevalence of parasitic agents and their potential involvement in\nthe development of acute appendicitis in southwestern Iran. Thus, the present study\nwas designed and carried out to evaluate the demographic information and\nhistopathological records of appendectomy specimens with a focus on\nparasitoses-related appendicitis during a 28-year period in Fars region, southwest\nIran.\n\nStudy Protocol\nIn this retrospective research, histopathological records of 13,013 appendectomy\ncases who had undergone surgeries for appendicitis at Dr. Ali Shariati Hospital,\naffiliated with the Fasa University of Medical Sciences were reviewed and data were\nretrieved for 28-year, from December 1993 to January 2021 in Fars Province.\nTherefore, the research team, which included pathologists and parasitologists,\nsearched manually the records. The demographical information, such as age, gender,\nand histopathological findings of appendectomies were extracted from each patient’s\nhistopathological record. The fundamental basis for the diagnosis of appendicitis\nwas histopathological examinations of the appendectomies. More than 6800 archived\nmicroscopic glass slides were also reviewed.\nThere were no exclusion criteria for this study. Based on whether or not there were\nparasite structures in the appendix lumen, patients’ pathological records were\ndivided into two groups. Age, gender, and histopathological findings of each case\nwere obtained from the patient’s surgical pathology records.\nAll the specimens were prepared once longitudinally and twice more transversely. All\nthe available microscopic slides were reviewed and classified by the two\nparasitologists based on the presence or absence of parasitic agents. The\nmicroanatomy, which reveals the parasite structures, was used to diagnose parasites.\nCases diagnosed with parasitic agents (e.g., helminths) were then, re-evaluated\npathologically for an inflammatory reaction by two expert pathologists. The various\nstages of acute appendicitis were designated as early acute, acute, suppurative,\ngangrenous, perforated, and not inflamed vermiform appendix. The diagnosis of acute\nappendicitis was made when a PMN infiltration was observed in the mucosa or deep\nlayers of the appendix. Eosinophilic appendicitis was also characterized by a\ndiffuse eosinophilic infiltration or by the presence of appendiceal granulomas of\nepithelial cells, fibroblasts, and many eosinophils having necrotic centers and\nsurrounded by diffuse eosinophilic infiltration. A normal appendix (without\ninflammation) was defined as one that was conducted to make an acute appendicitis\nclinical diagnosis, but in which the appendix was found to be normal on\nhistopathologic examination [ 1 ]. The number of\nsections and the gender of helminths were also analyzed.\nStatistical Analysis\nThe information was analyzed using Version 22 of the SPSS software. The Chi-Square\nand Mann-Whitney tests were utilized for comparison wherever appropriate.\n\n* \nData are presented as No. (%) and mean ± SD\n** \nAs no specific pathologic change\nFigure 1 . Cross-sections of Enterobius\nvermicularis in the lumens of appendices; H&E stain (×400).\n* \nHelminthiases as 73 enterobiasis and 1 ascariasis\nOverall, 8189 (62.9%) patients were male and 4824 (37.1%) were female. Patients’ age ranged from 2 to 98 years and the mean age was 24.68 ± 11.89 years. In histopathologic analysis, 9993 (76.8%) of the specimen\nshowed varying evidence of inflammation or unusual histopathologic findings, giving\na\n23.4% negative appendectomy rate. The most common inflammatory changes were 5,687\n(43.7%), 1,228 (9.4%), 670 (5.1%), 522 (4%), and 363 (2.8%) cases of acute\nappendicitis,\nsuppurative appendicitis, early acute appendicitis, gangrenous appendicitis, and\nperforated appendicitis respectively (Table- 1 ).\nMicroscopically, no viral inclusions, fungal elements, and histopathologic findings\nof bacterial causes were found microscopically. Parasitic infections were detected\nin 74\n(0.6%). Of 74 parasitoses, 73 (98.6%) were enterobiasis (Figure- 1 ) and 1 (1.4%) was ascariasis. No perforation or gangrene was\nseen in\nthe specimen containing E. vermicularis. The mean age of patients with parasitic\ninfections was 19.59 ± 10.71 years; 28 (37.8%) were males and 46 (62.2%) were\nfemales.\nParasites-infected cases were divided into two groups based on whether or not there\nwas\ninflammation. Group 1 was composed of 45 (60.8%) cases showing only helminth\ninfections\nwithout inflammation while the remaining 29 (39.2%) (Group 2) showed both helminth\ninfection and types of inflammation. Parasites-infected patients’ age ranged from 6\nto\n63 years and acute inflammation was frequently seen in the age group between 11 and\n20\nyears while no case was above 50 years. Microscopic investigation of tissue sections\nof\nappendices, including E. vermicularis demonstrated that infection was more frequent\nin\nfemales than in male appendices, with a ratio of 1 male to 1.6 females, indicating\nthat\nfemale E. vermicularis was found more frequently than men. There was no correlation\nbetween inflammation in the appendix and the gender of E. vermicularis (P˃0.05).\nOverall, E. vermicularis infection was present in 73 appendices (0.56%); of these,\n29\n(39.7%) showed a concurrent degree of inflammation, accounting for 0.2% of the study\npopulation. Note that in one case, E. vermicularis was associated with granulomatous\nappendicitis and in another case with eosinophilic appendicitis. Also, early acute\nappendicitis was seen in the case infected with Ascaris. Totaling, Table- 1\n  shows the clinicopathologic characteristics of patients who had undergone an\nappendectomy. The distribution of cases infected with parasites by gender, age, and\nhistopathologic findings is summarized in Table- 2\n  and\n 3 .\n\nEnterobiasis or oxyuriasis (Syn. Pinworm infection) is the most common helminthic\ninfection in children of those temperate regions with an estimated 4% to 28% of this\nage group being affected worldwide [ 3 ]. Although it is primarily an infection in\nyoung children, rapid maturation of the ova allows the infection to be readily\ntransmitted from child to child and from child to adult, in both family and\ninstitutional settings. In different studies, the prevalence of enterobiasis in Iran\nwas reported\namong all children, boys, and girls between 1.2%-66.1%, 2.3%-65.5%, and 1.7%-65.5%,\nrespectively [ 50 ]. In Iran, the prevalence of\npinworm\ninfection in appendicitis is low and there is no statistically significant relation\nbetween age\nor gender and this infection. Iran had a 1% (95 %CI=0.00-0.02) prevalence of E.\nvermicularis in\nappendicitis, with the greatest rate being 3% (95%CI=0.02-0.03) and the lowest rate\nbeing 0%\n(95%CI=0.00-0.01) [ 51 ]. Females had a\nsubstantially\nhigher prevalence of E. vermicularis than males (OR, 0.47; 95%CI, 0.38-0.59).\nDifferent\nbehavioral patterns and gender-based differences may be responsible for higher rates\nof\ninfection in females [ 2 ]. The role of this\norganism in the\npathogenesis of appendicitis has been debated since 1899 when the first report of\nthe occurrence\nof E. vermicularis was published [ 5 ]. There is\nlittle\ninformation available about the inflammatory complications of the vermiform appendix\ncaused by\nparasite etiologies in Iranian people. Therefore, this retrospective study aimed to\ndetermine\nthe prevalence of infectious agents, especially parasites in surgically removed\nappendices and\ntheir possible role in the pathogenesis of appendicitis through histopathological\nexaminations.\nIn this study, cases of parasitic appendicitis were examined and compared to cases\nin previous\nstudies completed over several years in different regions of the country.\nA retrospective study of 1590 removed appendices at Sina, Pars and Imam Khomeini\nhospitals in\nTehran between 1980 and 1990, revealed that 38 (2.39%) tissue specimens had E.\nvermicularis\ninfections [ 13 ]. In another study at Imam\nKhomeini\nHospital in Ahvaz, the capital of Khouzestan Province, Southwestern part of Iran, E.\nvermicularis was identified in 0.7% of 1,253 surgically removed appendices [ 19 ]. Moreover, a histopathological study of\nremoved appendices\nperformed by Mowlavi et al. in Khuzestan province, southwestern Iran, from 2001 to\n2003 revealed\nthat all 40 samples were positive for enterobiasis [ \n17 ].\nAlso, Fallah and Dehghani reviewed 5,981 appendectomy specimens in the Pathology\nDepartment at\nthe two teaching hospitals in Tabriz, northwestern Iran, from 2005 to 2009, and\nfound E.\nvermicularis in 38 (63.9%) cases [ 25 ]. A\nstudy by\nKazemzadeh et al. revealed that 0.3% of 1,533 surgically removed appendices were\ninfected with\npinworm at Al-Zahra Medical Centre in Isfahan, Iran [ 26 ].\nIn addition, a study in Kerman identified E. vermicularis in 0.7% of 5,048\nsurgically removed\nappendices from Iranian individuals [ 24 ].\nFurthermore, in\na study conducted in Qom Province in Central Iran between 2005 and 2016, it was\nobserved that\nthere were 31 parasitic appendicitis in 13,477 cases having primary appendicitis\n[ 45 ]. Also, Monajemzadeh et al. reported that\n2% of 947\nappendectomies were related to infections with E. vermicularis at the Pediatric\nCenter of\nExcellence, Tehran, Iran between 1988 and 2009 [ \n52 ]. In\nanother study, Hooshyar et al. reported the case of an 8-year-old girl with acute\nappendicitis\ndue to hyperinfection with E. vermicularis [ 1 ].\nTherefore,\nwhen determining the differential diagnosis of agents causing appendicitis, it is\nimportant to\nconsider the possibility of infection of the appendix with E. vermicularis. Mostly\nin children,\nthe presence of E. vermicularis in the appendix can cause abdominal pain mimicking\nfeatures of\nacute appendicitis or appendiceal colic with no histological evidence of acute\ninflammation\n[ 47 ].\nThe presumptive diagnosis of E. vermicularis infection is made clinically based on\nthe\nhistory of perianal itching and confirmed by examination of eggs or adults recovered\nfrom\nperianal skin material by the sticky tape technique [ 50 ].\nIn rare cases, this infection has been reported from other uncommon ectopic sites,\ne.g., the\nperitoneal cavity, lung, liver, kidney, and fallopian tubes, leading to severe\noutcomes and even\ndeath [ 2 ].\nIn ectopic locations, usually, a degenerating female is found, sometimes only\nremnants of\nuteri with eggs, or eggs alone [ 3 ]. Pathologic\ninvestigation typically reveals a chronic granulomatous inflammation with or without\ncore\nnecrosis that is encircled by neutrophils, eosinophils, and fibroblasts.\nCharcot-Leyden\ncrystals, giant cells, epithelioid cells, and macrophages may also seen [ 1 ]. E. vermicularis can cause signs and symptoms\nof acute appendicitis that\nclinically resemble tuberculous lymphadenitis [ \n2 ].\nSince the definitive diagnosis of appendicitis is achieved via histopathologic\ninvestigation,\nappendicitis is one of the most common acute surgical conditions of the abdomen\n[ 1 ][ \n2 ][ 3 ]. Obstruction of the appendix\nby one of the various\ncauses (e.g., fecaliths, infections such as parasites, tumors, and so on) leads to\nan\nincrease in luminal and intramural pressure, some with histopathologic findings and\nothers\nwith nonspecific findings that may require a thorough diagnostic assessment [ 2 ]. For example, E. vermicularis is found in\nabout 3% of\nthe appendices resected in the United States [ \n1 ][ 3 ]. The parasite is most often\nfound in the appendices\nof children between the ages of 7 to 11 years [ \n2 ]. In\nthe present study, depending on whether or not there were parasites in the appendix\nlumen,\nthe patients were split into two groups: in group 1 (n=74) we observed parasitic\ninfection,\nwhereas in patients of group 2 (n=12,939), no parasitic infestation was present. E.\nvermicularis was identified in 0.56% (n=73) appendectomy specimens, with previous\nstudies\nfrom Iran quoting between 0.2% and 2.9% [ 13 ][ 17 ][ 19 ][ 24 ][ 25 ][ 26 ][ 45 ].\nThis is\nlower in comparison with the prevalence reported from the conducted studies in some\nregions\nof Iran [ 13 ][ \n24 ].\nAccording to several studies, the prevalence of E. vermicularis-infected appendices\nin\nother countries was found to be between 0.2% to 15% [ \n5 ][ 6 ][ \n7 ][ 8 ][ \n9 ][ 10 ][ 11 ][ 12 ][ 14 ][ \n15 ][ 16 ][ 18 ][ 20 ][ 21 ][ \n22 ][ 23 ][ 27 ][ 28 ][ 29 ][ \n30 ][ 31 ][ 32 ][ 33 ][ 34 ][ \n35 ][ 36 ][ 37 ][ 38 ][ 39 ][ \n40 ][ 41 ][ 42 ][ 43 ][ 44 ][ \n46 ][ 47 ][ 48 ][ 49 ]. In recent\nyears,\nthe highest number of pinworm-infected appendectomy specimens (30/200; 15%) was\nreported\nfrom Palestine [ 41 ]. However, the worldwide\nrelationship of E. vermicularis infection with acute appendicitis varies widely from\n1.74% to 100%, hence making its relationship controversial [ 2 ]. Of 73 appendices containing E. vermicularis in this study,\n60.3%\n(44 specimens) belonged to females (Table- 2 ).\nDespite that, the majority of patients who had undergone appendectomy were male\n(n=8,189; 62.9%). This finding corresponds to several previous reports from Iran\n[ 30 ][ \n31 ] and\nother regions of the world [ 9 ][ 28 ][ 42 ].\nIt\nwas surprising to note that female pinworms were more commonly seen than males.\nAlthough\nfemale cases of E. vermicularis infection had a peak age distribution of 11-20 years\nold, there was no relationship between the gender of appendiceal E. vermicularis and\nE.\nvermicularis-infected patients and inflammation (P˃0.05). Furthermore, human\ninfections\nwith E. vermicularis appear to be becoming rarer in Iran. There have been clear\ndecreases in such prevalence over time, probably indicating general improvements in\nsanitation. Although E. vermicularis infection is the most common helminth parasite\nin\ntemperate regions [ 2 ], this event might\nexplain\nthe lower prevalence of the helminth in the present study.\n\nLastly, differential diagnosis of parasitic agents in the etiology of acute\nappendicitis was done properly in southwestern Iran.This event is the study of\nappendicitis due to infectious etiologies with a focus on parasitic agents on a\nlarge\nscale in southwestern Iran. Our review of the kinds of the literature shows that the\nexistence of this helminth in the appendiceal lumen can lead to pathologic changes\nranging from the normal appendix to acute or suppurative appendicitis, confirmed by\nour\nfindings.\nData from this study suggest that helminthic agents as the only infectious agents\neven with the low prevalence can be one of the probable causes of appendicitis\netiology in Iran and should be kept in mind during differential diagnosis. We\nsuspect, furthermore, that this number of tissue samples may be the tip of the\niceberg, with more cases remaining undetected. However, whether all intestinal\nparasitic infections lead to inflammation reactions in the appendix response is\ncontroversial and requires further investigation. These findings are in line with\nother studies carried out worldwide.\n\nThe authors state no conflict of interest.","source_license":"CC-BY-4.0","license_restricted":false}